{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T21:32:57Z","timestamp":1789421577896,"version":"build-2803163510"},"reference-count":62,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T00:00:00Z","timestamp":1736467200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["PO FEDER Comunitat Valenciana 2014\u20132020"],"award-info":[{"award-number":["PO FEDER Comunitat Valenciana 2014\u20132020"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018707","name":"HORIZON EUROPE Reforming and enhancing the European Research and Innovation system","doi-asserted-by":"publisher","award":["EU\u2010OPENSCREEN IMPULSE (Grant Agreement No. 101132028)"],"award-info":[{"award-number":["EU\u2010OPENSCREEN IMPULSE (Grant Agreement No. 101132028)"]}],"id":[{"id":"10.13039\/100018707","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100016386","name":"Conselleria de Innovaci\u00f3n, Universidades, Ciencia y Sociedad Digital, Generalitat Valenciana","doi-asserted-by":"publisher","award":["NextGeneration EU i+d+I funding through GVA Conselleria Innovaci\u00f3\u2010 Pol@Mets. Ref. MFA\/2022\/065"],"award-info":[{"award-number":["NextGeneration EU i+d+I funding through GVA Conselleria Innovaci\u00f3\u2010 Pol@Mets. Ref. MFA\/2022\/065"]}],"id":[{"id":"10.13039\/501100016386","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["PID2019\u2010108806RB\u2010I00"],"award-info":[{"award-number":["PID2019\u2010108806RB\u2010I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["PID2023\u2010152459OB\u2010I00"],"award-info":[{"award-number":["PID2023\u2010152459OB\u2010I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002704","name":"Fundaci\u00f3n Cient\u00edfica Asociaci\u00f3n Espa\u00f1ola Contra el C\u00e1ncer","doi-asserted-by":"publisher","award":["INVES211323CONE Junior AECC grant"],"award-info":[{"award-number":["INVES211323CONE Junior AECC grant"]}],"id":[{"id":"10.13039\/501100002704","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010665","name":"H2020 Marie Sk\u0142odowska-Curie Actions","doi-asserted-by":"publisher","award":["H2020\u2010MSCA\u2010ITN\u20102019 BIOMOLMACS (proposal n\u00b0 859416)"],"award-info":[{"award-number":["H2020\u2010MSCA\u2010ITN\u20102019 BIOMOLMACS (proposal n\u00b0 859416)"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Materials"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mitochondria play critical roles in regulating cell fate, with dysfunction correlating with the development of multiple diseases, emphasizing the need for engineered nanomedicines that cross biological barriers. Said nanomedicines often target fluctuating mitochondrial properties and\/or present inefficient\/insufficient cytosolic delivery (resulting in poor overall activity), while many require complex synthetic procedures involving targeting residues (hindering clinical translation). The synthesis\/characterization of polypeptide\u2010based cell penetrating diblock copolymers of poly\u2010L\u2010ornithine (PLO) and polyproline (PLP) (PLO<jats:sub>n<\/jats:sub>\u2010PLP<jats:sub>m<\/jats:sub>, n:m ratio 1:3) are described as mitochondria\u2010targeting nanocarriers. Synthesis involves a simple two\u2010step methodology based on N\u2010carboxyanhydride ring\u2010opening polymerization, with the scale\u2010up optimization using a \u201cdesign of experiments\u201d approach. The molecular mechanisms behind targetability and therapeutic activity are investigated through physical\/biological processes for diblock copolymers themselves or as targeting moieties in a poly\u2010L\u2010glutamic (PGA)\u2010based conjugate. Diblock copolymers prompt rapid cell entry via energy\u2010independent mechanisms and recognize mitochondria through the mitochondria\u2010specific phospholipid cardiolipin (CL). Stimuli\u2010driven conditions and mitochondria polarization dynamics, which decrease efficacy depending on disease type\/stage, do not compromise diblock copolymer uptake\/targetability. Diblock copolymers exhibit inherent concentration\u2010dependent anti\u2010tumorigenic activity at the mitochondrial level. The diblock copolymer conjugate possesses improved safety, significant cell penetration, and mitochondrial accumulation via cardiolipin recognition. These findings may support the development of efficient and safe mitochondrial\u2010targeting nanomedicines.<\/jats:p>","DOI":"10.1002\/adma.202411595","type":"journal-article","created":{"date-parts":[[2025,1,11]],"date-time":"2025-01-11T02:11:21Z","timestamp":1736561481000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Polyproline\u2010Polyornithine Diblock Copolymers with Inherent Mitochondria Tropism"],"prefix":"10.1002","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0347-7763","authenticated-orcid":false,"given":"Camilla","family":"Pegoraro","sequence":"first","affiliation":[{"name":"Pr\u00edncipe Felipe Research Center Polymer Therapeutics Lab.  Valencia 46012 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8336-316X","authenticated-orcid":false,"given":"Ekaterina","family":"Karpova","sequence":"additional","affiliation":[{"name":"Curapath  Av. Benjam\u00edn Franklin, 19, Paterna Valencia 46980 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0054-0608","authenticated-orcid":false,"given":"Yusuf","family":"Qutbuddin","sequence":"additional","affiliation":[{"name":"Max Planck Institute of Biochemistry  Am Klopferspitz 18 82152 Martinsried Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2293-0359","authenticated-orcid":false,"given":"Esther Masi\u00e1","family":"Sanchis","sequence":"additional","affiliation":[{"name":"Pr\u00edncipe Felipe Research Center Polymer Therapeutics Lab.  Valencia 46012 Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en C\u00e1ncer (CIBERONC) Instituto de Salud Carlos III  Madrid 28029 Spain"},{"name":"Pr\u00edncipe Felipe Research Center  Screening Platform Valencia 46012 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6332-2395","authenticated-orcid":false,"given":"Pavels","family":"Dimitrijevs","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis  Aizkraukles Street 21 Riga LV\u20101006 Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5734-2499","authenticated-orcid":false,"given":"Cristi\u00e1n","family":"Huck\u2010Iriart","sequence":"additional","affiliation":[{"name":"Experiments Division ALBA Synchrotron Light Source  Cerdanyola del Vall\u00e8s 08209 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7710-7864","authenticated-orcid":false,"given":"Svetozar","family":"Gavrilovi\u0107","sequence":"additional","affiliation":[{"name":"Max Planck Institute of Biochemistry  Am Klopferspitz 18 82152 Martinsried Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5875-2799","authenticated-orcid":false,"given":"Pavel","family":"Arsenyan","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis  Aizkraukles Street 21 Riga LV\u20101006 Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6106-4847","authenticated-orcid":false,"given":"Petra","family":"Schwille","sequence":"additional","affiliation":[{"name":"Max Planck Institute of Biochemistry  Am Klopferspitz 18 82152 Martinsried Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2476-3243","authenticated-orcid":false,"given":"Carles","family":"Felip\u2010Le\u00f3n","sequence":"additional","affiliation":[{"name":"Curapath  Av. Benjam\u00edn Franklin, 19, Paterna Valencia 46980 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7279-854X","authenticated-orcid":false,"given":"Aroa","family":"Duro\u2010Castano","sequence":"additional","affiliation":[{"name":"Curapath  Av. Benjam\u00edn Franklin, 19, Paterna Valencia 46980 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4196-0855","authenticated-orcid":false,"given":"Inmaculada","family":"Conejos\u2010Sanchez","sequence":"additional","affiliation":[{"name":"Pr\u00edncipe Felipe Research Center Polymer Therapeutics Lab.  Valencia 46012 Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en C\u00e1ncer (CIBERONC) Instituto de Salud Carlos III  Madrid 28029 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7771-3373","authenticated-orcid":false,"given":"Mar\u00eda J.","family":"Vicent","sequence":"additional","affiliation":[{"name":"Pr\u00edncipe Felipe Research Center Polymer Therapeutics Lab.  Valencia 46012 Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en C\u00e1ncer (CIBERONC) Instituto de Salud Carlos III  Madrid 28029 Spain"},{"name":"Pr\u00edncipe Felipe Research Center  Screening Platform Valencia 46012 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,1,10]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-020-00342-0"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201915826"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2024.115195"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2020.165808"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2017.07.009"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.bioconjchem.8b00732"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2011.10.077"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja052377g"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-011-0493-7"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2009.10.012"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/marc.202270036"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1039\/C9NR06187H"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.2558"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpcb.8b10864"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/mats.201100111"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0021889810015773"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.26434\/chemrxiv\u20102024\u20108jqp7"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsami.3c14908"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.langmuir.2c01435"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpcb.6b05604"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1039\/D3CP02411C"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2017.02.048"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.bioconjchem.0c00079"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biomac.0c00244"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsami.9b09395"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1021\/bc8002315"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2009.09.026"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2009.11.020"},{"key":"e_1_2_9_29_1","unstructured":"G. A.Morris Diffusion\u2010Ordered Spectroscopy (DOSY) In:R.K.Harris R.L.Wasylishen eds. EMagRes2009."},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1021\/ma5000392"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.26427"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.1c09456"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21218031"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.snb.2021.130537"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2020.00270"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2018.04.001"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.langmuir.7b01185"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2015.03.026"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1039\/C9CP02996F"},{"key":"e_1_2_9_40_1","doi-asserted-by":"crossref","unstructured":"A. J.Garc\u00eda\u2010S\u00e1ez D. C.Carrer P.Schwille Fluorescence\u00a0Correlation\u00a0Spectroscopy\u00a0for the study of membrane dynamics and organization in giant unilamellar vesicles In: (Eds:V.Weissig) Lipid\u2010Proteins Interactions vol 2: Biological membrane models Humana Press Totowa NJ2010 pp.493\u2013508.","DOI":"10.1007\/978-1-60761-447-0_33"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2014.06.010"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41557-018-0127-3"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpcb.3c07006"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgy148"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-50141-z"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.21769\/BioProtoc.3128"},{"key":"e_1_2_9_47_1","volume":"11","author":"Nguyen C.","year":"2019","journal-title":"Cancers"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1002\/wsbm.1595"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1186\/2049-3002-2-17"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12929-022-00859-2"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40200-021-00774-7"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202000767R"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aav1850"},{"key":"e_1_2_9_54_1","first-page":"1","volume":"9","author":"Biel T. G.","year":"2017","journal-title":"Oncotarget"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.13327"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1039\/C8CS00676H"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.actbio.2015.11.029"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-013-1198-x"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2018.03.004"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsanm.1c00987"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1021\/nl401365n"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1039\/C3SM52329B"}],"container-title":["Advanced Materials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/adma.202411595","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T23:13:05Z","timestamp":1759792385000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/adma.202411595"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,10]]},"references-count":62,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2025,2]]}},"alternative-id":["10.1002\/adma.202411595"],"URL":"https:\/\/doi.org\/10.1002\/adma.202411595","archive":["Portico"],"relation":{},"ISSN":["0935-9648","1521-4095"],"issn-type":[{"value":"0935-9648","type":"print"},{"value":"1521-4095","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,10]]},"assertion":[{"value":"2024-08-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"2411595"}}